Chronic obstructive pulmonary disease (COPD) includes conditions such as, e.g., chronic bronchitis and emphysema. COPD is estimated to affect about 64 million people worldwide, 15 million of which are in the United States alone, and is currently the third leading cause of death in the United States. The primary cause of COPD is inhalation of cigarette smoke, responsible for over 90% of COPD cases. The economic and social burden of the disease is substantial and is increasing.
Chronic bronchitis is characterized by chronic cough with sputum production. Due to airway inflammation, mucus hypersecretion, airway hyperresponsiveness, and eventual fibrosis of the airway walls, significant airflow and gas exchange limitations result. Emphysema is characterized by the destruction of the lung parenchyma. This destruction of the lung parenchyma leads to a loss of elastic recoil and tethering which maintains airway patency. Because bronchioles are not supported by cartilage like the larger airways, they have little intrinsic support and therefore are susceptible to collapse when destruction of tethering occurs, particularly during exhalation.
Acute exacerbations of COPD (AECOPD) often require emergency care and inpatient hospital care. AECOPDs are defined by a sudden worsening of symptoms (e.g. increase in or onset of cough, wheezing, and sputum changes) that typically last for several days, up to a couple weeks. Bacterial infection, viral infection, or pollutants typically trigger AECOPDs, which manifest quickly into airway inflammation, mucus hypersecretion, and bronchoconstriction, which cause significant airway restriction.
Despite relatively efficacious drugs (long-acting muscarinic antagonists, long-acting beta agonists, corticosteroids, and antibiotics) that treat COPD symptoms, a particular segment of patients known as “frequent exacerbators” often visit the emergency room and hospital with exacerbations and also have a more rapid decline in lung function, poorer quality of life, and greater mortality.
The autonomic nervous system provides constant control over airway smooth muscle, secretory cells, and vasculature, and therefore, some conventional methods have attempted to treat COPD symptoms by treating portions of the autonomic nervous system. For example, some conventional methods used to treat COPD include various anticholinergic drugs. Although sympathetic and parasympathetic branches of the autonomic nervous system innervate the airways, the parasympathetic branch dominates, especially with respect to control of airway smooth muscle and secretions. Cholinergic nerve fibers arise in the nucleus ambiguus in the brain stem and travel down the vagus nerve (right and left vagus nerves) and synapse in parasympathetic ganglia, which are located within the airway wall. These parasympathetic ganglia are most numerous in the trachea and mainstem bronchi, especially near the hilus and points of bifurcations, with fewer ganglia dispersed in distal airways. From these ganglia, short post-ganglionic fibers travel to airway smooth muscle and submucosal glands. Acetylcholine (ACh), the parasympathetic neurotransmitter, is released from post-ganglionic fibers and acts upon M1- and M3-receptors on smooth muscles and submucosal glands to cause bronchoconstriction and mucus secretion, respectively. Acetylcholine may additionally regulate airway inflammation and airway remodeling, and it may contribute significantly to the pathophysiology of obstructive airway diseases.
Wide varieties of stimuli (e.g., cigarette smoke, mechanical stimuli, and other irritants) are able to elicit reflex cholinergic bronchoconstriction through activation of sensory receptors in the larynx or airways. These sensory receptors primarily include rapidly adapting receptors (RARs) and C-Fibers, both of which have nerve endings in the epithelium. Activation of these afferent nerves causes a cholinergic reflex that is known to result in bronchoconstriction and an increase in airway mucus secretion through the activation of muscarinic receptors on airway smooth muscle cells and submucosal glands.
Bronchial hyperreactivity (BHR) may be present in a considerable number of COPD patients. Various reports have suggested BHR to be present in between ˜60% and 94% of COPD patients. This “hyperreactivity” could be due to a “hyperreflexivity”. However, there are several logical mechanisms by which parasympathetic drive may be overactivated in inflammatory disease. First, inflammation is commonly associated with overt activation and increases in excitability of vagal C-fibers in the airways that could increase reflex parasympathetic tone. Secondly, airway inflammation and inflammatory mediators have been found to increase synaptic efficacy and decrease action potential accommodation in bronchial parasympathetic ganglia; effects that would likely reduce their filtering function and lead to prolonged excitation. Thirdly, airway inflammation has also been found to inhibit muscarinic M2 receptor-mediated auto-inhibition of acetylcholine release from postganglionic nerve terminals. This would lead to a larger end-organ response (e.g., smooth muscle contraction) per a given amount of action potential discharge. Fourthly, airway inflammation has been associated with phenotypic changes in the parasympathetic nervous system that could affect the balance of cholinergic contractile versus non-adrenergic non-cholinergic (NANC) relaxant innervation of smooth muscle.
Because airway resistance varies inversely with the fourth power of the airway radius, BHR is believed to be a function of both bronchoconstriction and inflammation. Inflammation in the airway walls reduces the inner diameter (or radius) of the airway lumen, thus amplifying the effect of even baseline cholinergic tone.
Denervation and nerve stimulation therapies for the bronchial tree have been proposed to reduce bronchial hyperresponsiveness and the probability of AECOPD events. However, these denervation therapies are often non-selective in the region of the airway, either axially or radially, in where to treat to achieve the desired denervation effect. Rather, full circumferential coverage is often targeted in one or more locations throughout the airway in attempt to ensure the treatment region encompasses the targeted nerve(s). This may subject the patient to a greater risk of acute side effects such as inflammation and/or mucus production (and the associated airflow limitation associated with each) as well as other risks than may be required for effective denervation. Additionally, these existing therapies do not provide a real-time assessment of the efficacy of a treatment and thus do not provide patient customized therapy.
Accordingly, a need exists for selectively identifying optimal location for treatment of airway tissue and targeting nerves in the airway to optimize therapy location and to minimize unnecessary treatment to a patient's airway to minimize risk of short-term or long-term side effects.